Amyotrophic lateral sclerosis (ALS) is an adult onset, rapidly fatal, neurodegenerative disease of unknown etiology. Studies have indicated a higher prevalence of ALS among veterans than among civilians, and in 2008, ALS was declared a fully compensable condition by the Department of Veterans Affairs (VA). The VA funds research projects such as the VA Biorepository Brain Bank (VABBB) to support ALS research and improve clinical care. Establishing large national cohorts essential for ALS research is limited by the low prevalence (6-8 cases per 100,000) and short survival time (3-5 years) of persons with ALS (PALS). This is particularly true for efforts to develop biorepositories that collect central nervous system (CNS) tissue samples annotated with clinical information essential to biomedical ALS research. Although a number of mouse models have been developed to study ALS, these models are limited and the need for research quality human CNS tissue for genomic and proteomic research in ALS is critical. The VABBB is presently the only national prospective cohort study and CNS tissue bank in the U.S. that is enrolling and conducting ongoing follow-up on veterans with ALS. The VABBB is a multi-site collaboration among VA Boston Healthcare System (VABHS) and the Southern Arizona VA Healthcare System (SAVAHCS). The VABBB utilizes the strengths across the Boston and Tucson sites in enrollment, assessment, tissue banking operations, neuropathological diagnosis, medical informatics and data management. The VABBB cohort is notable for its size (over 300 PALS), the amount and quality of CNS tissue and clinical data available, and especially for the relatively long duration and slow disease progression in this unique cohort. Tissue and clinical data from the VABBB are available for international distribution to qualified researchers. In this application, we seek to further our support of cutting edge ALS research and enhance the value of VA?s investment in the VABBB. Over the next four years our specific aims are: 1) To continue and further enhance the VABBB as the nation?s only national prospective cohort study and central nervous system (CNS) tissue/biofluid bank supporting international ALS research; 2) Leverage the resources and staffing of the VABBB to conduct new state-of-the-art genetic, biomarker, environmental exposure and neuropathological analyses on banked biofluid and tissue samples; and 3) To provide a state-of-the-art characterization of cognitive and behavioral dysfunction in our cohort to support research on the pathophysiology and clinical management of ALS. Specific Aim 1 will involve 1) generation of a larger and more diverse CNS tissue collection from Veteran PALS along with spousal and Veteran controls; 2) enhanced antemortem assessment of enrollees and postmortem biofluid and tissue collection and analyses; and 3) development of an international outreach program to promote the use of our tissue and data by ALS researchers. In Specific Aim 2, we will 1) conduct whole genome sequencing on our tissue; 2) cryopreserve live microglia from post-mortem tissue for cellular studies; 3) analyze samples for current and newly discovered ALS biomarkers (e.g., urinary p75ECD) and environmental exposures to enhance the value of our tissue in validating biomarkers and environmental exposures against ALS neuropathology; 4) assess our CSF quality to promote a diversity of ALS research, and 5) conduct neuropathological analyses with rigorous quantitative and semi-quantitative measurements of the histopathological, immunohistochemical, and anatomical findings to examine emerging links between head trauma, ALS, and overlapping pathologies such as CTE. Regarding Specific Aim 3, we will enhance our longitudinal cognitive/behavioral telephone/mail assessment of our cohort to facilitate clinicopathological and genetic studies of ALS. The availability of high quality fixed and frozen CNS tissue and data from the VABBB will facilitate research into genetic and environmental risk factors and clinical pathological relationships in ALS.